There is growing evidence that the host genetic make-up of an individual is a strong determinant of HIV/AIDS susceptibility. We have integrated genetics, immunology, and evolution, and used them as powerful tools to (a) uncover complex host gene-gene interactions that influence HIV-1 pathogenesis in vivo; (b) determine the relative contribution to these determinants to the HIV-1 epidemic at the population level; (c) translate these findings to real life practical issues such as improved clinical care of patients via genetic-based prognostication of AIDS as well as design and evaluation of vaccine trials; and (d) shed light on the immune correlates of a protective anti-HIV response in vivo that can be modeled for rational vaccine design. In the current application we will test the overall hypothesis that (I) expression of members of the CD4 - CD4 ligand - CCR5 - CCR5 ligand nexus, including relevant transducers of coreceptor signals, will alter HIV/AIDS susceptibility (aim #1); (II) expression of candidate genes that influence T cell dynamics and regulation will alter HIV/AIDS susceptibility (aim #2); and (III) HIV/AIDS susceptibility is linked to the gene dose of alpha-defensins (aim #3). In aim #4, we will explore means to place host genetics in a broader framework, and will determine their influence on AIDS prognostication, T cell dynamics and other public health aspects of the epidemic. Thus, this proposal seeks funds to support a collaborative study to explore the genetic mechanisms underlying HIV/AIDS susceptibility by amalgamating the unique skills and resources of two different research teams, namely genetics (UTHSCSA), epidemiology/virology/statistics (WHMC), population genetics (Utah) and immunolog/virology (Vanderbilt). This study will utilize pre-existing, anonymous, unlinked human specimens. IRB approval for genetic study of these specimens has been previously obtained under expedited review authorized by 45 CFR 46.110, and is a continuation of an existing approved IRB proposal. [unreadable] [unreadable]